Mechanisms by which angiotensin-receptor blockers increase ACE2 levels.

We read with interest the well-balanced Comment by Zheng and colleagues (COVID-19 and the cardiovascular system. Nat. Rev. Cardiol. 17, 259–260; 2020)[1] and their Reply (Reply to: ‘Interaction between RAAS inhibitors and ACE2 in the context of COVID-19’. Nat. Rev. Cardiol. 17, 313–314; 2020)[2] to the Correspondence written by Mourad and Levy (Interaction between RAAS inhibitors and ACE2 in the context of COVID-19. Nat. Rev. Cardiol. 17, 313; 2020)[3].

We have reported the capacity of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) to increase the left ventricular levels of Ace2 mRNA when given to normotensive rats either under normal conditions[4] or following coronary artery ligation[5]. This work revealed the existence of a negative feedback mechanism in which the angiotensin-converting enzyme 2 (ACE2)–angiotensin-(1–7)–Mas receptor axis counterbalances the pathological effects of angiotensin II[6]. In their Reply[2], Zheng and colleagues suggest that the mechanism underlying the increase in levels of cardiac Ace2 mRNA and ACE2 activity by these drugs was undetermined; we wish to clarify that we did elucidate the mechanism by which these medications augment the expression of ACE2 (refs[7-9]).

In these studies, the inhibitory effect of angiotensin II on the transcription of Ace2 in cultured cerebellar or medullary astrocytes from rats was prevented by exposure to losartan or valsartan but not PD123319 (a blocker of angiotensin II receptor type 2)[7]. A similar finding was obtained in cultured cardiomyocytes and cardiac fibroblasts from neonatal rats[8]; in these in vitro experiments, the inhibitory effect of angiotensin II on the transcription of Ace2 and on ACE2 enzymatic activity was replicated by the treatment of cardiomyocytes with exogenous endothelin 1 (ref.[8]). The inhibitory effect of angiotensin II on Ace2 transcription is mediated by activation of extracellular signal-regulated kinase 1 (ERK1; also known as MAPK3) and ERK2 (also known as MAPK1)[8,9]. In addition, treatment of rat neonatal cardiomyocytes in vitro with atrial natriuretic peptide reversed the downregulation of Ace2 transcription induced by angiotensin II or endothelin 1 (ref.[8]). We have also shown that angiotensin II reduces Ace2 transcription and ACE2 activity in rat aortic smooth muscle cells in vitro via activation of a MAPK phosphatase pathway[9], as confirmed by others[10].

These experiments show that Ace2 expression in cardiac tissues in rats depends on the balance and concentration of regulatory molecules. We appreciate the opportunity to highlight the cellular signalling mechanisms by which ARBs increase Ace2 expression and ACE2 activity, especially given that ACE inhibitors and ARBs have opposite effects on the plasma and tissue concentrations of angiotensin II and angiotensin-(1–7) (ref.[6]).